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Adenina , Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Piperidinas , Medicina de Precisão , Pirazóis , Pirimidinas , Humanos , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Adenina/análogos & derivados , Adenina/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Medicina de Precisão/métodos , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
INTRODUCTION: Traditionally, the success of chronic lymphocytic leukemia (CLL) treatment has been primarily assessed based on clinical outcomes, such as disease response, progression-free survival (PFS), and overall survival (OS). However, the evolution of treatment approaches recognizes the importance of a patient-centered perspective that includes factors directly affecting patients' quality of life and overall well-being. AREAS COVERED: Studies addressing the impact of targeted agents on improving either OS or other endpoint surrogates were selected using PubMed and MEDLINE platforms. Our search also included studies that considered patient-centric endpoints such as health-related quality of life and patient-reported outcomes (PROs). EXPERT OPINION: The changing landscape of CLL treatment underscores the importance of continually exploring various endpoints to thoroughly define treatment success. Beyond conventional metrics such as OS and surrogate endpoints, namely, PFS, time to next treatment (TTNT), and measurable residual disease (MRD) assessment, it becomes crucial to integrate enhanced comorbidity evaluations and patient-centered viewpoints into a CLL success roadmap.Subsequent investigations ought to concentrate on enhancing current surrogate endpoints, discerning their contextual significance, and exploring innovative indicators of treatment efficacy and safety. Given the dynamic nature of CLL and the heterogeneity among patient groups, personalized strategies are essential, taking into account individual traits and patient preferences.
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Leucemia Linfocítica Crônica de Células B , Qualidade de Vida , Leucemia Linfocítica Crônica de Células B/terapia , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/diagnóstico , Humanos , Resultado do Tratamento , Medidas de Resultados Relatados pelo Paciente , Comorbidade , Assistência Centrada no Paciente , Biomarcadores Tumorais , BiomarcadoresRESUMO
To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7-58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was -0.4 months (95% CI: -0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: -0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: -1.6 months; 95% CI: -2.4 to -0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: -0.9 months; 95% CI: -1.7 to -0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP.
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Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients' clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3-4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.
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Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , Antineoplásicos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológicoRESUMO
Chronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio-demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W&W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage). Health-related quality of life was assessed with the EQ-5D-5L, EORTC QLQ-C30 and QLQ CLL-16. Previously treated patients had longer disease duration (7 vs. 5 years), higher prevalence of serious comorbidities (45.5% vs. 36.2%) and high-risk molecular markers (unmutated IGHV 55.6% vs. 17.1%; TP53 mutation 15.2% vs. 4.0%). Health-related quality of life scores were similar between groups. In the DCE, W&W patients rated "possible occurrence of infections" highest (relative importance [RI] = 36.2%), followed by "treatment and relevant duration" (RI = 28.0%) and "progression-free survival (PFS)" (RI = 16.9%). Previously treated patients rated "treatment and relevant duration" highest (RI = 33.3%), followed by "possible occurrence of infections" (RI = 28.8%), "possible occurrence of organ damage" (RI = 19.4%), and "PFS" (RI = 9.8%). Concern over infection was rated highest overall; unexpectedly PFS was not among the most important criteria in either group, suggesting that the first COVID-19 pandemic wave may have influenced patient preferences and concerns about CLL therapy options.
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Leucemia Linfocítica Crônica de Células B , Adulto , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Preferência do Paciente , Qualidade de Vida , Estudos Transversais , PandemiasRESUMO
In the modern era of Chronic Lymphocytic Leukemia (CLL) targeted therapy, the loss of p53 function due to genetic abnormalities remains a significant challenge. This is because even targeted agents, which are currently the mainstay of treatment for CLL, do not directly target p53 or restore its disrupted pathway. Consequently, resistance to therapy and unfavorable clinical outcomes often accompany these p53-related abnormalities. An essential goal of future clinical research should be to address the ostensibly "undruggable" p53 pathway. Currently, multiple therapeutic approaches are being explored to tackle TP53 dysfunction and improve outcomes in high-risk CLL. These approaches include the use of oncoprotein murine double minute 2 inhibitors, small-molecule p53 reactivators, exportin 1 (XPO1) inhibitors, and ataxia-telangiectasia mutated and Rad3-related (ATR) inhibitors. Combinations of these p53-targeting strategies, along with established novel therapies such as B-cell receptor or B-cell lymphoma-2 (BCL-2) inhibitors, may shape the future of therapeutic trials in this challenging-to-treat disease.
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Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Humanos , Animais , Camundongos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Antineoplásicos/uso terapêuticoRESUMO
Pooled analysis of six mature phase 3 trials (RESONATE2, ILLUMINATE, ALLIANCE041202, ELEVATE-TN, CLL14, and GLOW) evaluating Bruton's tyrosine kinase inhibitors (BTKis) and venetoclax-based treatments suggests that these agents have reduced but not completely eliminated the overall survival (OS) gap between elderly chronic lymphocytic leukemia (CLL) patients and the age and sex-matched general population (AGMGP).
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Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Humanos , Idoso , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adenina/uso terapêutico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
INTRODUCTION: Chronic lymphocytic leukemia (CLL) management has witnessed a transformative shift with the advent of time-limited venetoclax and anti-CD20 monoclonal antibody (mAb) regimens, as exemplified by the groundbreaking MURANO and CLL14 trials. AREA COVERED: This article delves into the long-term follow-up data of fixed duration (FD) venetoclax combined with anti-CD20 mAb across various lines of CLL therapy. The data discussed here, not yet available in current literature, was unveiled at the 23rd European Hematological Association (EHA) congress held in Frankfurt in June 2023. EXPERT OPINION: Combinations of venetoclax with anti-CD20 mAbs represent a compelling therapeutic option due to their finite treatment duration and remarkable achievement of undetectable minimal residual disease (uMRD). This not only ensures more enduring responses but also presents a manageable toxicity profile that suits a broad spectrum of CLL patients, including those who are elderly or less medically fit.Importantly, the integration of venetoclax/anti-CD20 mAb FD regimens may diminish the likelihood of CLL patients developing target mutations. This, in turn, enhances the potential for eliciting secondary clinical responses upon retreatment with venetoclax. Additionally, from an economic perspective, the cost-effectiveness of targeted therapy may further advocate for the selection of FD therapy as a frontrunner in CLL treatment.
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Hodgkin lymphoma (HL) has become 1 of the most curable cancers. Therefore, rigorous assessment of health-related quality of life (HRQoL) and symptom burden of these patients is essential to support informed clinical decisions. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group previously developed the EORTC Quality of Life Questionnaire (QLQ) Hodgkin Lymphoma 27. This paper reports the final results of an international study by the EORTC group to develop a HRQoL disease-specific measure for these patients: the EORTC QLQ-HL27. Patients with a confirmed diagnosis of HL (N = 381) were enrolled from 12 countries and completed the EORTC QLQ-C30, QLQ-HL27, and a debriefing questionnaire at baseline (any time after diagnosis). A subset completed a retest (n = 126) or responsiveness-to-change analyses (RCA) second measurement (n = 98). Psychometrics were evaluated. Confirmatory factor analysis showed an acceptable fit of the 27 items of the QLQ-HL27 on its 4 scales (symptom burden, physical condition/fatigue, emotional impact, and worries about health/functioning). Test-retest reliability, convergent validity, known-group comparisons, and RCA find satisfactory results. Symptom burden and fatigue was higher among patients on treatment (with 36%-83% reporting at least a few problems) compared with those who had completed treatment (19%-61% reporting at least a few problems). Prevalence of worries about health and functioning (reporting at least some worry) was similar for patients on treatment (51%-81%) vs those who had completed treatment (52%-78%). Implementation of the EORTC QLQ-HL27 in research and clinical applications will increase sensitivity of HRQoL assessment in patients with HL. High quality data generated through use of this questionnaire are expected to facilitate clinical decision making in the HL setting.
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Doença de Hodgkin , Qualidade de Vida , Humanos , Qualidade de Vida/psicologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/terapia , Reprodutibilidade dos Testes , Inquéritos e Questionários , Fadiga/etiologiaRESUMO
Ibrutinib, the first-in-class Bruton's tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine-rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu's advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden.
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Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Health-related quality of life (HRQOL) is a critical aspect to consider when making treatment decisions for patients with non-Hodgkin-lymphoma (NHL). This international study by the European Organisation for Research and Treatment of Cancer (EORTC) tested the psychometric properties of two newly developed measures for patients with high-grade (HG)- and low-grade (LG)-NHL: the EORTC QLQ-NHL-HG29 and the EORTC QLQ-NHL-LG20 to supplement the core questionnaire (EORTC QLQ-C30). METHODS: Overall, 768 patients with HG-NHL (N = 423) and LG-NHL (N = 345) from 12 countries completed the QLQ-C30, QLQ-NHL-HG29/QLQ-NHL-LG20 and a debriefing questionnaire at baseline, and a subset at follow-up for either retest (N = 125/124) or responsiveness to change (RCA; N = 98/49). RESULTS: Confirmatory factor analysis showed an acceptable to good fit of the 29 items of the QLQ-NHL-HG29 on its five scales (symptom burden [SB], neuropathy, physical condition/fatigue [PF], emotional impact [EI], and worries about health/functioning [WH]), and of the 20 items of the QLQ-NHL-LG20 on its four scales (SB, PF, EI, and WH). Completion took on average 10 minutes. Test-retest reliability, convergent validity, known-group comparisons, and RCA find satisfactory results of both measures. A total of 31%-78% of patients with HG-NHL and 22%-73% of patients with LG-NHL reported symptoms and/or worries (e.g., tingling in hands/feet, lack of energy, and worries about recurrence). Patients reporting symptoms/worries had substantially lower HRQOL compared to those without. DISCUSSION: The use of the EORTC QLQ-NHL-HG29 and QLQ-NHL-LG20 questionnaires in clinical research and practice will provide clinically relevant data to better inform treatment decision-making. PLAIN LANGUAGE SUMMARY: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group developed two questionnaires. These questionnaires measure health-related quality of life. The questionnaires are for patients with high-grade or low-grade non-Hodgkin lymphoma. They are called the EORTC QLQ-NHL-HG29 and QLQ-NHL-LG20. The questionnaires are now internationally validated. This study demonstrates that the questionnaires are reliably and valid, which are important aspects of a questionnaire. The questionnaires can now be used in clinical trials and practice. With the information gathered from the questionnaires, patients and clinicians can better evaluate treatments and discuss the best choice for a patient.
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Linfoma não Hodgkin , Neoplasias , Humanos , Qualidade de Vida/psicologia , Reprodutibilidade dos Testes , Inquéritos e Questionários , PsicometriaRESUMO
Chronic lymphocytic leukaemia (CLL) is a malignancy of clonally expanded antigen-switched, neoplastic, mature B cells. CLL is characterised by a variable degree of immunosuppression and secondary hypogammaglobulinemia. B-cell depleting therapies have historically been deployed with a proportion of patients becoming resistant to multiple lines of treatment with an associated worsening of immunosuppression and heightened infection risk. Advances in molecular diagnostics and the development of new therapies targeting Bruton's tyrosine kinase and B-cell lymphoma-2 have resulted in novel insights into the cellular mechanisms associated with an increased infection risk and T-cell escape from the complex tumour environment found in CLL. Generally, immunoglobulin replacement therapy with polyvalent human immunoglobulin G (IgG) is indicated in patients with recurrent severe bacterial infections and low IgG levels, but there is no consensus on the threshold IgG level for initiation of such therapy. A proportion of CLL patients have residual IgG production, with preserved quality of the immunoglobulin molecules, and therefore a definition of 'IgG quality' may allow for lower dosing or less frequent treatment with immunoglobulin therapy in such patients. Immunoglobulin therapy can restore innate immunity and in conjunction with CLL targeted therapies may allow T-cell antigen priming, restore T-cell function thereby providing an escape from tumour-associated autoimmunity and the development of an immune-mediated anti-tumour effect. This review aims to discuss the mechanisms by which CLL-targeted therapy may exert a synergistic therapeutic effect with immunoglobulin replacement therapy both in terms of reducing tumour bulk and restoration of immune function.